This invention relates to 3-pyridyloxymethyl heterocyclic ether compounds which control chemical synaptic transmission; to therapeutically-effective pharmaceutical compositions of these compounds; and to the use of said compositions to selectively control synaptic transmission.
Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission. The control of synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane. Presynaptic control of membrane excitability results from the direct effect an active compound has upon the organelles and enzymes present in the nerve terminal for synthesizing, storing, and releasing the neurotransmitter, as well as the process for active re-uptake. Postsynaptic control of membrane excitability results from the influence an active compound has upon the cytoplasmic organelles that respond to neurotransmitter action.
An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a fuller explanation of chemical synaptic transmission refer to Hoffman et al., xe2x80x9cNeurotransmission: The autonomic and somatic motor nervous systems.xe2x80x9d In: Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, 9th ed., J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, 1996, pp. 105-139).
Typically, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that elicits an all-or-none action potential in a nerve axon. The action potential propagates to the nerve terminal where ion fluxes activate a mobilization process leading to neurotransmitter secretion and xe2x80x9ctransmissionxe2x80x9d to the postsynaptic cell. Those cells which receive communication from the central and peripheral nervous systems in the form of neurotransmitters are referred to as xe2x80x9cexcitable cells.xe2x80x9d Excitable cells are cells such as nerves, smooth muscle cells, cardiac cells and glands. The effect of a neurotransmitter upon an excitable cell may be to cause either an excitatory or an inhibitory postsynaptic potential (EPSP or IPSP, respectively) depending upon the nature of the postsynaptic receptor for the particular neurotransmitter and the extent to which other neurotransmitters are present. Whether a particular neurotransmitter causes excitation or inhibition depends principally on the ionic channels that are opened in the postsynaptic membrane (i.e., in the excitable cell).
EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na+ and K+), whereas IPSPs are the result of stabilization or hyperpolarization of the membrane excitability due to a increase in permeability to primarily smaller ions (including K+ and Clxe2x88x92). For example, the neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na+ and K+. At other synapses, such as cardiac cells, acetylcholine can be inhibitory, primarily resulting from an increase in K+ conductance.
The biological effects of the compounds of the present invention result from modulation of a particular subtype of acetylcholine receptor. It is, therefore, important to understand the differences between two receptor subtypes. The two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, op. Cit.).
The responses of these receptor subtypes are mediated by two entirely different classes of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g. Na+, K+ and Ca++) through the neuronal membrane. In contrast, muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates. Thus, the biological consequences of nicotinic acetylcholine receptor-activation are distinct from those of muscarinic receptor activation. In an analogous manner, inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are distinct and different from those arising from muscarinic receptor inhibition.
As indicated above, the two principal sites to which drug compounds that affect chemical synaptic transmission may be directed are the presynaptic nerve terminal and the postsynaptic membrane. Actions of drugs directed to the presynaptic site may be mediated through presynaptic receptors that respond to the neurotransmitter which the same secreting structure has released (i.e., an autoreceptor), or through a presynaptic receptor that responds to another neurotransmitter (i.e., a heteroreceptor). Actions of drugs directed to the postsynaptic membrane mimic the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a postsynaptic receptor.
Classic examples of drugs that modulate postsynaptic membrane excitability are the neuromuscular blocking agents which interact with nicotinic acetylcholine-gated channel receptors on skeletal muscle, for example, competitive (stabilizing) agents, such as curare, or depolarizing agents, such as succinylcholine.
In the central nervous system, postsynaptic cells can have many neurotransmitters impinging upon them. This makes it difficult to know the precise net balance of chemical synaptic transmission required to control a given cell. Nonetheless, by designing compounds that selectively affect only one pre- or postsynaptic receptor, it is possible to modulate the net balance of all the other inputs. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders.
Knowing how specific neurotransmitters act in the CNS allows one to speculate about the disorders that may be treatable with certain CNS-active drugs. For example, dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals. Many aspects of the phannacology of dopamine have been reviewed by Roth and Elsworth, xe2x80x9cBiochemical Pharmacology of Midbrain Dopamine Neuronsxe2x80x9d, In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds., Raven Press, N.Y., 1995, pp 227-243). Patients with Parkinson""s disease have a primary loss of dopamine containing neurons of the nigrostriatal pathway, which results in profound loss of motor control. Therapeutic strategies to replace the dopamine deficiency with dopamine mimetics, as well as administering pharmacologic agents that modify dopamine release and other neurotransmitters have been found to have therapeutic benefit (xe2x80x9cParkinson""s Diseasexe2x80x9d, In: Psychopharmacology: The Fourth Generation of Procress, op. cit, pp 1479-1484).
New and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in important, but as yet poorly controlled, disease states or behavior models. For example, dementia, such as is seen with Alzheimer""s disease or Parkinsonism, remains largely untreatable. Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention-Deficit Disorder (ADD). Specific agents for treatment of these and related disorders are few in number or non-existent.
A more complete discussion of the possible utility as CNS-active agents of compounds with activity as cholinergic ligands selective for neuronal nicotinic receptors, (i.e., for controlling chemical synaptic transmission) may be found in U.S. Pat. No. 5,472,958, to Gunn et al., issued Dec. 5, 1995, which is incorporated herein by reference.
Existing acetylcholine channel agonists are therapeutically sub-optimal in treating the conditions discussed above. For example, such compounds have unfavorable pharrnacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability and tolerability (e.g., nicotine). In addition, other agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al., in: Nicotine Psychopharmacolog, S. Wonnacott, M. A. H. Russell, and I. P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor and Francis: New York, 1988; pp 333-336).
Various heterocyclic 2-pyrrolidinyloxy-substituted compounds with analgesic and hypotensive activities have been disclosed by Scheffler et al. (U.S. Pat. No. 4,643,995) and Tomioka et al. (Chem. Pharm. Bull, 38:2133-5, 1990).
Certain other 2-pyridyloxy-substituted compounds are disclosed inter alia by Engel et al. in U.S. Pat. No. 4,946,836 as having analgesic activity.
Various other compounds having a pyrrolidine or azetidine moiety substituted at the 3-position with a heterocycloxy group have also been disclosed (cf. U.S. Pat. No. 4,592,866 to A. D. Cale; U.S. Pat. No. 4,705,853 to A. D. Cale; U.S. Pat. No. 4,956,359 to Taylor et al.; and U.S. Pat. No. 5,037,841 to Schoehe et al. and European patent application EP296560A2, to Sugimoto et al.).
Certain nicotine-related compounds having utility in enhancing cognitive function have been reported by Lin in U.S. Pat. No. 5,278,176, issued Jan. 11, 1994. Also, 2-(nitro)phenoxy compounds with similar fintion have been reported by Gunn et al., U.S. Pat. No. 5,472,958, issued Dec. 5, 1995.
In the PCT Patent Application W094 08992 of Abreo et al., published Apr. 28, 1994, are disclosed, inter alia, various 3-pyridyloxy-heterocyclic compounds that are either unsubstituted or mono-substituted on the pyridine ring with groups such as Br, Cl, F, hydroxyl, C1-C3-alkyl or C1-C3-alkoxy, such compounds also described as having utility in enhancing cognitive function.
In accordance with the principal embodiment of the present invention, there is provided a class of 5-substituted 3-pyridyloxymethyl heterocyclic ether compounds which are selective and potent neuronal nicotinic cholinergic compounds useful in controlling synaptic transmission.
The compounds of the present invention are represented by formula (I): 
or a pharmaceutically acceptable salt thereof wherein n is selected from 1, 2 or 3.
The substituents R1 is selected from the group consisting of hydrogen, allyl, and alkyl of one to six carbon atoms.
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl, fluorine, chlorine, ethenyl, and phenyl.
The linking group, L, is absent or is selected from the group consisting of alkylene of one to six carbon atoms, xe2x80x94Cxe2x89xa1Cxe2x80x94(C0-C6-alkyl)-, "Parenopenst"CHxe2x95x90CH"Parenclosest"p(C0-C6-alkyl)- where p is one or two 
where M is selected from xe2x80x94CH2xe2x80x94, and xe2x80x94NHxe2x80x94.
The substituent R3 is selected from the group consisting of a) hydrogen, b) alkyl of one to eight carbon atoms, c) alkeynl of 2-6 carbon atoms d) haloalkyl of one to six carbon atoms, e) hydroxyalkyl of one to six carbon atoms, f) alkoxy of one to six carbon atoms, g) amino, h) alkylamino of one to six carbon atoms, hxe2x80x2) azacycle attached to L through a nitrogen atom, i) dialkylamino in which the two alkyl groups are independently of one to six carbon atoms, j) phenyl, k) naphthyl, 1) biphenyl, m) furyl, n) thienyl, o) pyridinyl, p) pyrazinyl, q) pyridazinyl, r) pyrimidinyl, s) pyrrolyl, t) pyrazolyl, u) imidazolyl, v) indolyl, w) thiazolyl, x) oxazolyl, y) isoxazolyl, z) thiadiazolyl, aa) oxadiazolyl, bb) quinolinyl, cc) isoquinolinyl, and cc) any of b) or j) through cc) above substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl in which the alkoxy and alkyl portions are independently of one to six carbon atoms, alkoxyalkoxyl in which the alkoxy portions are independently of one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms.
Alternatively, Lxe2x80x94R3 is Oxe2x80x94CH2xe2x80x94R4, wherein R4 is selected from CH3OCH2xe2x80x94, or from substituents i) through bb) above, which may be substituted with one or two substituents independently selected from the group consisting of alkyl of one to six carbon atoms, haloalkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, alkoxyalkyl in which the alkoxy and alkyl portions are independently of one to six carbon atoms, alkoxyalkoxyl in which the alkoxy portions are independently of one to six carbon atoms, halogen, cyano, hydroxy, amino, alkylamino of one to six carbon atoms, carboxyl, and alkoxycarbonyl of two to six carbon atoms.
The above definitions of the various linking and substituent groups in the compounds of the present invention are limited by the provisos that i) when L is absent, R3 may not be hydrogen, alkyl of one to eight carbon atoms, alkoxy of 1-6 carbons, amino, alkylamino or dialkylamino; ii) when L is absent and R3 is hydrogen, R2 is selected from ethenyl, unsubstituted phenyl, and phenyl substituted as defined in bb) above; iii) when L is alkylene, R3 may not be hydrogen or alkyl;
iv) when L is 
xe2x80x83then R3 is selected from alkyl of one to eight carbon atoms, a carbocyclic aryl erocyclic aryl ring selected from hxe2x80x2) i), j), k), l), m), n), o), p), q), bb), and cc) as defined above, and any of i), j), k), 1), m), n),o), p), bb) and cc) as substituted as defined in dd) above; v) when L is 
xe2x80x83and M is xe2x80x94CH2xe2x80x94, then R3 may not be hydrogen; and
vi) f) through y) above maya substituted as defined in z) above by no more than one alkylamino, carboxyl, or alkoxycarbonyl substituent.